Early‐onset reduced bone mineral density in patients with pyruvate kinase deficiency
Authors: Hanny Al‐Samkari, Rachael F. Grace, Andreas Glenthøj, Oliver Andres, Wilma Barcellini, Frédéric Galactéros, Kevin H. M. Kuo, D. Mark Layton, Marta Morado Arias, Vip Viprakasit, Yan Dong, Feng Tai, Peter Hawkins, Sarah Gheuens, Jaime Morales‐Arias, Keely S. Gilroy, John B. Porter, Eduard J. van Beers
Journal: American Journal of Hematology (2023)

To the Editor: Pyruvate kinase (PK) deficiency is a rare disease caused by mutations in the PKLR gene encoding the red blood cell (RBC) PK enzyme, leading to defective glycolysis and chronic hemolytic anemia.1 The estimated prevalence of clinically diagnosed PK deficiency ranges from 3.2 to 8.5 per million in Western populations; however, the disease may be underdiagnosed and the true global prevalence may be higher. Patients with PK deficiency can develop multiple complications including gallstones, pulmonary hypertension, and iron overload regardless of transfusion status.2 Similar to other hemolytic anemias, PK deficiency can also lead to reduced bone mineral density (BMD), which may result in premature osteopenia, osteoporosis, and bone fractures.1, 2 A PK deficiency natural history registry (N = 254) found bone fractures and bone deformities in 17% and 9% of patients,1 respectively. The mechanisms leading to reduced BMD in patients with PK deficiency may be similar to those of other hemolytic disorders that are associated with BMD loss, including: erythroid hyperplasia widening the marrow spaces; iron overload and iron chelation, potentially resulting in dysregulated osteoclast and osteoblast function and increased bone resorption3; endocrine disruptions, which may interfere with normal bone growth and bone mineral deposition3; and genetic factors. Low BMD (Z-score < −1.0) is common in other hemolytic disorders such as thalassemia and sickle cell disease, with an estimated prevalence of 77% and 80%, respectively.4, 5 In thalassemia, increasing age has also shown to be a strong predictor of low BMD.4 The prevalence of low BMD in patients with PK deficiency has not been systematically assessed, and the mechanisms leading to BMD loss are not well defined.1 Therefore, the overall patient burden of BMD-related complications is poorly understood. To better characterize BMD abnormalities in PK deficiency, this study evaluated the prevalence of low BMD as assessed by dual-energy X-ray absorptiometry (DXA) scans and patient medical history review in pooled pretreatment baseline data from three global clinical trials of mitapivat in patients (≥18 years) with PK deficiency (Figure S1). DRIVE-PK (N = 52; NCT02476916) was a phase 2, randomized, open-label study of patients who were not regularly transfused.6 ACTIVATE (N = 80; NCT03548220) was a phase 3, randomized, placebo-controlled study of patients who were not regularly transfused.7 ACTIVATE-T (N = 27; NCT03559699) was a phase 3, single-arm, open-label study of patients who were regularly transfused.8 Baseline DXA scans were done at screening for ACTIVATE and ACTIVATE-T, and at screening or up to 3 months before the start of the study for DRIVE-PK. Scans were done locally for all three studies, and were interpreted centrally for ACTIVATE and ACTIVATE-T and locally for DRIVE-PK. T- and Z-scores, derived from DXA scans at three locations (total femur [combined neck and total hip], femoral neck, and spine), were used to classify patients into BMD categories according to standard definitions. A T-score compares a patient's BMD with that of an average healthy 30-year-old and is used to diagnose osteopenia and osteoporosis in men aged ≥50 years and women of nonchildbearing potential (here, a score of ≥ − 1.0 at all locations was classified as normal BMD, <−1.0 to > − 2.5 at one or more locations as low BMD or osteopenia, and ≤ −2.5 at one or more locations as very low BMD or osteoporosis). A Z-score compares a patient's BMD with that of a person of the same age and sex and is used to diagnose low BMD in men aged <50 years and women of childbearing potential (here, a score of ≤ − 2.0 indicates low BMD). The findings reported in this study show the proportion of patients with low BMD based on worst DXA scan T- or Z-score, depending on age and childbearing status, at one or more of three locations. In addition, the patient's medical history was collected at screening and reviewed for prior diagnosis of osteopenia or osteoporosis, concomitant use of anti-osteoporotic medications, history of bone fracture, and number of RBC units transfused and transfusion episodes in the previous year. All findings reported here are summarized as descriptive statistics and stratified based on age and childbearing status. A total of 159 patients enrolled in DRIVE-PK, ACTIVATE, and ACTIVATE-T; 157 patients had baseline DXA scans available and were included in this analysis (Tables S1 and S2): 19.7% of patients (N = 31) were men ≥50 years or women of nonchildbearing potential and 80.3% of patients (N = 126) were men <50 years or women of childbearing potential. Among the 31 men ≥50 years and women of nonchildbearing potential, 27 patients (87.1%) had a baseline worst T-score of <−1.0 in one or more of three locations, indicating low BMD, including all (6 of 6) patients who were regularly transfused and 84.0% (21 of 25) of patients who were not regularly transfused. Six patients (19.4%) had a baseline worst T-score of ≤ − 2.5 in one or more of three locations, consistent with osteoporosis, and 21 patients (67.7%) had a baseline worst T-score of <−1.0 to > − 2.5 in one or more of three locations, consistent with osteopenia (Figure 1A). Data for BMD by location are also reported in Figure 1A and mean baseline T-scores in Figure S2. Only 13 patients (41.9%) among all men ≥50 years and women of nonchildbearing potential had a medical history of osteopenia or osteoporosis. Among those with a T-score of <−1.0 (n = 27), the median age was 55 years (range, 34–78); 2 of 27 patients (7.4%) had received anti-osteoporotic medications, and 4 of 27 patients (14.8%) had a history of bone fractures (Table S2). Among the 126 men <50 years and women of childbearing potential, 41 patients (32.5%) had a baseline worst Z-score of ≤ − 2.0 in one or more of three locations indicating low BMD (Figure 1B), including 6 of 20 who were regularly transfused and 35 of 106 who were not regularly transfused. Forty patients (31.7%) of the men <50 years and women of childbearing potential had a medical history of osteopenia or osteoporosis. Among the patients with a Z-score of ≤ − 2.0 (n = 41), the median age was 28 years (range, 18–48); 5 of 41 patients (12.2%) had received anti-osteoporotic medications, and 3 of 41 patients (7.3%) had a history of bone fractures. In this large cohort analysis, BMD abnormalities were systematically characterized in patients with PK deficiency. This pooled analysis found that, when T-score and Z-score criteria were appropriately applied according to age and childbearing status, 43.3% of patients had low or very low BMD. Additionally, low BMD was highly prevalent regardless of transfusion frequency or age category. Given that the median age of this cohort was 34 years, this represents a strikingly high rate of early-onset BMD in patients with PK deficiency. This study does have limitations to consider. Firstly, as there have been no formal studies to date defining the optimal diagnostic methods for osteopenia and osteoporosis in patients with PK deficiency, this analysis adhered to conventions broadly used in other populations (e.g., patients with thalassemia). Secondly, DXA scans for the DRIVE-PK study were not read centrally and therefore may be subject to inter-rater variability. Key strengths of this analysis were the systematic collection of DXA scans as part of three clinical trials, as well as the large number of patients included for this rare disease. In conclusion, this analysis found that low BMD is highly prevalent in patients with PK deficiency with a relatively young median age, to a much greater degree than previously reported. These findings highlight the clinical burden of PK deficiency and suggest that early monitoring with DXA scans is warranted to promptly diagnose and treat BMD abnormalities in these patients. Future clinical research is needed to understand how current management techniques and novel therapies may impact BMD in this population. Conflict of interest: Hanny Al-Samkari has received consultancy fees from Agios, Argenx, Dova/Sobi, Moderna, Novartis, Rigel Pharmaceuticals, Inc., Forma Therapeutics, and research funding from Agios, Amgen, Dova. Rachael F. Grace has received research funding from Agios, Novartis, Dova, and consultancy fees from Agios, Principia Biopharma, Inc. Andreas Glenthøj has received consultancy fees and is an advisory board member for Agios, bluebirdbio, Celgene, Novartis, has received a research grant from Alexion, and has received an honoraria grant from Novo Nordisk. Oliver Andres has no competing financial interests. Wilma Barcellini has received honoraria from Agios, Alexion, Novartis, has received research funding from Agios, and has a board membership or advisory committee for Bioverativ, Incyte. Frédéric Galactéros has a board membership or advisory committee for Addmedica. Kevin H. M. Kuo has received consultancy fees from Agios, Alexion, Apellis, bluebirdbio, Celgene, Pfizer, Novartis, has received honoraria from Alexion, Novartis, has membership of an entity's Board of Directors or advisory committees for Bioverativ, Agios, and has received research funding from Pfizer. D. Mark Layton has received consultancy fees from Agios, Novartis, and has membership of an entity's Board of Directors or advisory committees for Agios, Novartis, Cerus. Marta Morado Arias has received honoraria and other grants from Sanofi Genzyme. Vip Viprakasit has received consultancy fees, honoraria, research funding, and speakers bureau from Bristol-Myers Squibb, and has received research funding and consultancy fees from Agios, Ionis Pharmaceuticals Inc., La Jolla Pharmaceutical. Yan Dong is an employee of Agios, and is a stockholder in Agios, Bristol-Myers Squibb, Infinity Pharmaceuticals, Jazz Pharmaceuticals. Feng Tai, Peter Hawkins, Sarah Gheuens, Jaime Morales-Arias, Keely S. Gilroy, are employees of and stockholders in Agios. John B. Porter has received honoraria from Agios, bluebirdbio, Celgene, La Jolla Pharmaceutical, Protagonist Therapeutics, Silence Therapeutics, Vifor, and consultancy fees from Agios, bluebirdbio, Celgene. Eduard J. van Beers is an advisory member for Agios, and has received research funding from Agios, Novartis, Pfizer, RR Mechatronics. The authors would like to thank the patients, their families, and all investigators involved in this study. Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments, was provided by Michelle Mancher, MPH, supported by Agios Pharmaceuticals, Inc. according to Good Publication Practice guidelines (Link). The sponsor was involved in the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. However, the authors assume ultimate responsibility for the opinions, conclusions, and data interpretation within the manuscript. Each subject was required to sign an informed consent form (ICF) to participate in the study. A legally authorized representative could have consented on behalf of a subject who was otherwise unable to provide informed consent, if acceptable to and approved by the site and/or the site's institutional review board (IRB)/independent ethics committee (IEC). An ICF that explained the procedures of the study, including the potential hazards, was reviewed and approved by the IRB/IEC before its use. The ICF was read by and explained to each subject or their legally authorized representative before entering the study. Each subject had ample opportunity to ask questions and was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Each subject or representative received a signed and dated copy of the ICF. The study was conducted in accordance with the Declaration of Helsinki. Clinicaltrials.gov. NCT02476916, NCT03548220, NCT03559699. (see http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html). Data S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.